Abstract

Thomas Edison's invention of the incandescent light bulb in 1879 ushered in the second industrial revolution, allowing people to extend typical daytime behavior well into the night. Millions of people are now up at night, working night shifts or simply staying up late. Yet this revolutionary change may pose new and unexpected challenges to human health. Only very recently have serious concerns about the potential effects of shift work emerged, largely attributed to the disruption of human circadian rhythms by light at night. Today, almost 15 million Americans regularly work alternate shifts, including evening (4.7 M), night (3.2 M), and rotating shifts (2.5 M) or other employer-arranged irregular schedules. Observational studies have consistently associated rotating shift work with increases in cancer risk, prompting the WHO in December 2007 to classify night shift work a carcinogen class 2A (probable carcinogen) - the main operating mechanism being assumed circadian disruption by means of melatonin suppression.

The ‘biological clock’ in the suprachiasmatic nucleus (SCN) in the hypothalamus controls numerous functions that follow regular, daily patterns (or ‘circadian’ rhythms), including: the sleep/wake cycle; body temperature; blood pressure; renal function; hormone secretion; and immune function. In addition, the SCN appears to be crucial for behavioral and physiological adaptation to 24-hour food availability. Environmental lighting powerfully influences this circadian system in humans. Light entrains the biological clock, as the SCN receives environmental dark/light information directly from the retina. This mechanism appears to have evolved to detect changes in day length/season (for functions like migration and hibernation). Melatonin is a hormone and marker of circadian rhythmicity intimately linked to the circadian system that demonstrates cancer-protective properties. Mechanisms for the cancer-protective activity of melatonin relate to its influence on other hormones, as well as melatonin's antioxidant and immune-modulatory effects which appear to also slow down the aging process and, more generally, delay mortality. Melatonin production is acutely sensitive to light exposure. It is currently thought that nightly exposure to artificial light erodes and shifts the natural melatonin peak, thereby increasing disease risk. Not surprisingly, this complex circadian system has a genetic component: Mutations in the fruit fly Drosophila melanogaster that affect the circadian clock, and later, human twin studies of abnormal circadian phenotypes showing that much of morning and evening preference is heritable, led to the identification and characterization of clock genes responsible for circadian behavior.

Our group has demonstrated that rotating night work increased not only breast, but also colorectal and endometrial cancer risk in two independent prospective cohorts, the Nurses' Health Study cohorts. We ruled out chronic stress as a confounding factor that might explain the observed associations in night workers. Besides our work on shift work and cancer risk, we have done fundamental work in developing and validating melatonin as a biomarker of circadian disruption. In support of the above mentioned underlying mechanisms of the association between night work and cancer risk, we showed that this biomarker was indeed associated with breast cancer risk, thus corroborating the initial findings from the observational studies of night workers. We explored, which dietary and lifestyle factors, besides night work, influence melatonin production. Centered around our work on the relationship between shift work and cancer risk is a novel theory that we developed, stating (and subsequently proving) that the effects of night work extend beyond hormonally sensitive cancers, as put forward by the initial melatonin hypothesis.

Several strategies could reduce the health risk associated with shift work-induced circadian disruption. First, genetic screening tests may identify vulnerable populations, as variations in certain clock (or other) genes may make a person more susceptible to the effects of light at night. The efficacy of such targeted strategies will become evident in part through our most current work, whose results I will report. Second, the use of exogenous melatonin in night workers is being discussed, but we are far from knowing whether melatonin is safe in primary prevention of circadian rhythm disorders induced by shift work. However, we have conducted new work to examine the potential of oral melatonin to affect biomarkers related to breast cancer risk and I will report results from this double-blind randomized trial of 4 months of 3 mg melatonin daily compared to placebo. This trial was only recently completed by 95 postmenopausal women with a prior history of Stage 0-III breast cancer who had completed active cancer treatment (including hormonal therapy). Third, determining the effect of light sources with respect to their short wavelength (blue) light (the most disruptive to our circadian system) on the circadian system might help determine new prevention strategies and I will report to that effect. Lastly, we believe that determining which factors relate to shift schedules and what aspects of shift schedules are most detrimental to health is the next frontier in shift work and disease prevention. To date, few studies have examined how specific aspects of shift schedules including length, frequency of rotation, and hours worked per week interact and relate to health and safety. Moreover, how long working hours influence health and safety outcomes in older workers, women, persons with pre-existing health problems, and workers with hazardous occupational exposures is not well understood. Whether there is an age at which people are particularly vulnerable to the effects of circadian disruption also remains unclear. Future research would benefit from a clear and complete description of work schedules and their effects on human health.